Abstract Disclosure: M. Sedghian: None. M. Flanagan: None. D. Pinkhasova: None. K. Selk: None. G. Moloney: None. Background: Atypical femur fractures (AFF) occur along the shaft of the femur extending from the subtrochanteric region proximally to the distal femoral metaphysis. These fractures have an increased incidence in patients taking bisphosphonates and denosumab for osteoporosis and develop as stress reactions in the lateral cortex of the femoral shaft (beaking). However, few cases that meet the characteristics of these fractures have occurred in patients who have never used antiresorptive drugs. We present a case with a history of long-term proton pump inhibitor (PPI) use and possible association with AFF. Clinical Case: The patient is a 68-year-old female with a past medical history of hypothyroidism who presented to the emergency department (ED) after an atraumatic femur fracture and consequently ground level fall. The patient reported experiencing a distinctive cracking sound in her femur while leaning over to wash her feet, resulting in a fall that prompted her to seek immediate care in the ED. Upon initial evaluation, radiographic imaging was significant for displaced left mid-femoral diaphyseal fracture and right femur lateral cortex thickening consistent with AFF. Labs were consistent with elevated PTH to 100.7 [18.4-80.1], Vit D2 1,25 (OH)2 <8 pg/mL, Vit D 25OH 34 ng/ml [30-100], and Calcium level of 9.5. Upon further history taking, the patient stated that she has been taking PPIs intermittently for more than 10 years. She denied a history of bisphosphonate and denosumab exposure, non-Hodgkin's lymphoma, rheumatoid arthritis, and COL1A2 variant mutations as main predisposing factors for atypical femur fractures. She had potential steroid exposure for less than a year before hospitalization as she was on "adrenal complex" from her functional medicine provider. The patient underwent open reduction and internal fixation of the left femur with placement of intramedullary nail and prophylactic fixation with placement of intramedullary nail of the right femur as there was radiographic evidence of beaking. Discussion/Conclusion: Several studies suggested a possible association between PPIs and fracture risk, especially hip fractures, but the relationship remains contentious. Overall, PPIs are positively associated with elevated fracture risk in multiple studies. Increased gastrin production and hypochlorhydria are the two main mechanisms that affect bone remodeling, decreasing bone turnover, impairing calcium absorption, and altering homocysteine levels through impairment of folate and vitamin B12 absorption.This case supports a potential association between long-term PPI use and atypical femur fractures. There have been other case reports that also highlight this potential risk of PPI use. This shows the importance of more comprehensive research on this topic as the number of patients on long-term PPIs is growing in outpatient settings. Presentation: 6/2/2024